Future Use of Selective Estrogen Receptor Modulators and Aromatase Inhibitors I

Home , Anastrozole, Arzoxifene, Idoxifene

4402s Vol. 7, 4402s-4410s, December 2001 (Suppl.) Clinical Cancer Research

Anthony Howell 2 The two groups of endocrine therapies for which there has been CRC Department of Medical Oncology, University of Manchester, the greatest development recently are the SERMs 3 and the AIs. Christie Hospital, Manchester M20 4BX, United Kingdom SERMs Available or in Development The first SERMs to be used clinically were pharmacolog- Abstract ical doses of estrogen analogues, for example, DES (1), dienes- Selective estrogen receptor modulators (SERMs) may trol (2), and ethinylestradiol (3). Randomized trials comparing act as estrogens or antiestrogens depending on the cell and high-dose estrogens with tamoxifen showed them to be equally tissue targets. The triphenylethylene SERMs are repre- active (reviewed in Ref. 3). After long-term follow-up, the sented by tamoxifen and toremifene and a new agent with a largest trial of this type showed a survival advantage for DES novel carboxylic acid side chain (GW5638). Because of compared with tamoxifen (4). We recently reported a study of isomerization in the triphenylethylene molecule, "fixed DES involving 30 patients who had had on average four previ- ring" SERMs were introduced. The major one in develop- ous endocrine therapies. Thirty percent of patients responded to ment is the benzothiophene arzoxiphene (LY353381), which DES for a median period of 49 weeks, suggesting that high-dose is now in Phase llI clinical trial versus tamoxifen. A fourth estrogen therapy may well have been abandoned prematurely as group of SERMs is based on the estrogen molecule and an endocrine treatment (5). comprises the so-called "pure" antiestrogen ICI 182,780 High-dose estrogens were largely replaced by tamoxifen as (fulvestrant, Faslodex) and a new oral analogue just entering soon as the latter was shown to be potentially equally active but trials, SR16234. The steroidal aromatase inhibitors [AIs less toxic (6). Several attempts have been made to introduce (40H androstenedione and exemestane)] inactivate aro- more active analogues of tamoxifen, but randomized clinical matase, whereas the triazole AIs (anastrozole and letrozole) trials and Phase II studies have not shown superiority for the inhibit the enzyme via the heme prosthetic group. Thus, analogues idoxifene, droloxifene, or TAT 59 compared with there are two groups of AIs that show relative non-cross- tamoxifen, and these have therefore been abandoned for breast resistance in advanced breast cancer and four groups of cancer treatment (7). Toremifene remains available but shows SERMs that also show a high degree of non-cross-resistance. no advantage over tamoxifen for either adjuvant treatment (8) or With six different treatments and six or more clinical situ- the treatment of advanced disease (9). A new triphenylethylene ations (prevention, neoadjuvant, adjuvant, and first- and (GW5638), which may be more active than the others because second-line treatments for advanced disease) in which they of a novel carboxylic acid side chain, looks promising in pre- may be used, the possible combinations of treatment are clinical studies and is currently entering clinical trials (Refs. 10 enormous. At present, we have few clinical pointers to op- and 11; Fig. 1). timal sequence of treatments. Now that most of the appro- Isomerization around the double bond in the triphenyleth- priate comparative trials have been performed, it may be the ylene molecule was thought to be problematical, and thus a time to initiate novel approaches. These include alternating series of so-called "fixed ring" structures have been introduced, and sequential treatments, preferably with treatments including raloxifene, EM800 (EM652 is the metabolite), and changed before overt progression occurs. arzoxifene (LY353381). The activity of these agents in Phase II trials in advanced breast cancer is shown in Table 1. Raloxifene Introduction and EM800 are moderately active but have been withdrawn Although endocrine therapy has been in use clinically for from development for breast cancer treatment, whereas arzox- over 100 years, we still have a great deal to learn concerning the ifene (formerly known as SERM III) looks promising and is in optimal way to use this modality for breast cancer, not only a Phase III trial versus tamoxifen as first-line therapy in ad- because the appropriate trials to determine the best approach to vanced disease. A recent Phase I/II study suggests that arzox- treatment have not all been performed to date, but also because ifene may be non-cross-resistant with tamoxifen, although more new endocrine agents are being constantly introduced that re- data are required to be certain (12). Wyeth-Ayerst also have a quire additional studies on how to integrate the new with the old. fixed ring SERM in early clinical development (ERA-923). Wakeling and Bowler (13) developed the estrogen ana-

Presented at the First International Conference on Recent Advances and Future Directions in Endocrine Therapy for Breast Cancer, June 3 The abbreviations used are: SERM, selective estrogen receptor mod- 21-23, 2001, Cambridge, MA. ulator; AI, aromatase inhibitor; DES, diethylstilbestrol; ER, estrogen 2 To whom requests for reprints should be addressed, at CRC Depart- receptor; CR, complete response; PR, partial response; SD, stable dis- ment of Medical Oncology, University of Manchester, Christie Hospital, ease; E2, estradiol; WR, withdrawal response; HRT, hormone replace- Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom. ment therapy.

OH High dose OH 'Oestrogens' ~ OH H04,~l~J~ H Stllboestrol Ethinyloestradiol

/ CO2H ~N~ O Triphenyl ethylenes

CI Tamoxifen Toremlfene GW 5638

'Fixed ring'

HO~ OH Raloxifene (LY 156,758) EM 652 (SCH 57068) Arzoxlfene (LY 353,381)

H2CO~.~ R OR.L

"-.~lb Oestradiol .~T T C,I~0, ~o "-~""" ""sK analogues HO 0II HO SK-{CH~,-N-CH-CH-IOH2).- 80~-1CH2)5- E I I I

ICl 182,780 SR 16234 ZK-191703 Fig. 1 Structures of compounds in use or in clinical development in the four classes of SERMs described in the text.

Table I First- and second-line treatment with "fixed ring" compounds EM-800 (Ref. 40) Raloxifene (Ref. 41) Arzoxifene (Ref. 42) Arzoxifene (Ref. 12) (SCH57050) 20 or 40 mg (LY156758) 300 mg (SERM III) (LY353381) 20-50 mg First-line therapy CR 1 0 28 0 PR 5 4 8 SD 10 3 t7 8 PD 27 14 43 Total response 16/43 (37%) 7/21 (33 %) 45/88 (51%) 16/49 (33 %) Second-line therapy (prior tamoxifen) 43 6 0 14 All responded

logue ICI 182,780 (fulvestrant, Faslodex) as a new class of anastrozole as second-line therapy for advanced breast cancer antiestrogen because it was felt that to pursue the development (14-16). The latter results are promising because all patients in of analogues of triphenylethylenes as breast cancer treatment these two Phase III trials had been treated previously with would not be productive. ICI 182,780 (Fig. 1) has been shown tamoxifen. The results of a trial of tamoxifen versus ICI 182,780 to be non-cross-resistant with tamoxifen and to be equivalent to as first-line therapy for advanced disease will be available later

Table 2 Non-cross-resistance between classes of SERMs Table 3 Non-cross-resistance between classes of AIs Classes of SERMs Classes of AIs Pharmacologic estrogens Nonsteroidal--anastrozole--letrozole Triphenylethylenes--tamoxifen Steroidal---4OH androstenedione---exemestane Fixed ring--Arzoxifene (SERM3) Examples of non-cross-resistance between classes Steroidal--ICI 182,780 Anastrozole --> 4OH (Ref. 45) Examples of non-cross resistance between classes Letrozole ~ 4OH (Ref. 45) TAM ---->ICI 182780 (Ref. 14) Anastrozole ~ Exemestane (Ref. 44) TAM ~ Arzoxifene (Ref. 43) TAM ----> Stilbestrol (Ref. 4)

A B o o 100--~ 85.2% Steroidal A! 1~1761 OH CH 2

Formestane Exemestane 60-1 .... ~ 62.7% a

N-N 40- N N-N NA+B 43.7% 35.9% 500 Nonsteroidal AI CH H~ ~J~ 20 NC-CHsI -,~ CH.= t-CN HO CN 0 Anastrozole Letrozole 0 5 lb 1st 2 ~ 3 rd Years Line of Therapy Fig. 2 Two classes of modern AIs: steroidal and nonsteroidal Als. Fig. 3 A, 10-year results of the effectiveness of 5 years of adjuvant tamoxifen on relapse-free survival. Just over one-third of relapses are prevented by tamoxifen. B, estimated "clinical benefit" (CR + PR + SD 6/12) after first-, second-, and third-line endocrine therapies for ad- this year and are awaited with great interest. Other estrogen vanced disease. analogues entering clinical trials are SR16234 and ZK191703, which look promising in preclinical studies and, unlike ICI 182,780, are said to be p.o. bioavailable (Fig. 1). Thus, we have four groups of SERMs available for breast Many clinical studies indicate that SERMs and AIs show cancer treatment. These are high-dose estrogens (particularly limited cross-resistance. This, together with evidence of non- DES), triphenylethylenes (tamoxifen), the fixed ring structures cross-resistance within the SERM and AI classes, indicates that (particularly arzoxiphene), and steroidal compounds (particular- we have potentially a large number of therapeutic options to ly ICI 182,780). There is strong evidence from clinical trials that explore for the treatment of all stages of breast cancer. However, DES and ICI 182,780 are non-cross-resistant with tamoxifen, with six groups of agents (perhaps seven if ovarian ablation is and there is some evidence that arzoxifene is non-cross-resistant included) and six or seven clinical scenarios (prevention, neo- with tamoxifen (Table 2). Non-cross-resistance is probably re- adjuvant, adjuvant, and first-, second-, and third-line therapy for lated to differences in conformation of the ER induced by the advanced disease), the problem of finding the optimal sequences SERMs of each class and is of great importance clinically or combinations of endocrine agents is enormous. because we may have four different SERMs for the treatment of early and advanced breast cancer. Effectiveness of Current Treatments Although we have a pleasing number of endocrine thera- AIs Clinically Available or in Development pies in development, the effectiveness of those in use at present The first AI to enter the clinic was aminoglutethimide (Fig. is limited. The results of adjuvant treatment with tamoxifen and 2; Ref. 17). This agent caused adrenal suppression and had other commonly used first-, second-, and third-line agents for ad- toxicities and has been replaced by two other triazole com- vanced disease are shown in Fig. 3. Effects are seen in patients pounds (anastrozole and letrozole). Two steroidal compounds with ER+ tumors only because endocrine therapy is clearly are also in clinical use (40H androstenedione and exemestane). ineffective for the 30-40% of patients with ER- tumors, leav- Anastrozole, letrozole, and exemestane showed superiority over ing only 60-70% of patients to be treated by this approach. Five megestrol acetate as second-line therapy for advanced breast years of tamoxifen reduces recurrences from 63% to 76% at 10 cancer (18-20). Importantly, all three agents show superiority years of follow-up (25). This represents a 35% reduction in the over tamoxifen as first-line treatment for advanced disease (21- proportion of women who relapsed up to 15 years after surgery. 24). The steroidal and nonsteroidal classes of AIs show prom- Clearly, this means that 65% of women who have a relapse are ising degrees of non-cross-resistance (Table 3). not helped by tamoxifen or that recurrence is only delayed.

At relapse, a maximum of about 60% of patients respond to T47-D cells the best treatment available at this stage, which appears to be an 200 - Reddel & Sutherland 1984 AI. This 60% includes CRs and PRs (CR + PR) and SD for 6 months or more. SD gives a similar survival benefit as a partial remission and in all modern trials is included as a "response" m

(26, 27). The overall response (CR + PR + SD) has been called ,4,,,Ie 160 C E2 "clinical benefit." The median duration of response to first-line 8 therapy for advanced disease is about 12-18 months. Nonre- sponders to endocrine therapy do not usually respond to a c = 120 second therapy (see exception below) and are usually treated 0 u with chemotherapy. Approximately 40% of responders to first 0 therapy will obtain clinical benefit from a second endocrine o treatment for a median response duration of about 6-18 months. 80 ...... Approximately 20-30% of responders to second therapy will have clinical benefit from a third therapy for a median of 6-12 40 im months. Some patients can spend many years in multiple remissions, but the majority of patients with relapsed ER+ tumors 20 unfortunately have no benefit or only a temporary benefit from endocrine therapy (Fig. 3). o t0-,0 t0-. + o-;.sx o Concentration-M Mechanisms of Endocrine Responsiveness Fig. 4 Dose-response curves for E2 and tamoxifen using T47D cells With four classes of SERMs and two classes of AIs avail- grown in serum-free medium (after Ref. 32). able, can we improve response rates and response durations in advanced disease and prevent relapse in the adjuvant situation? At this point, it is worth stopping to ask the difficult questions of how endocrine therapies work and why tumors become using receptor-positive human tumor cell lines grown in vitro in resistant to them. In particular, it is important to understand serum-free media (to remove endogenous hormones and inhib- potential mechanisms of multiple responses and how we can itors found in serum) and give us an indication of the potential extend the duration and number of responses. In endocrine- in vivo mechanisms of resistance. An early example of such responsive tumors, estrogen is the major mitogenic hormone dose-response curves was reported by Reddel and Sutherland acting via the ER and stimulates growth through the synthesis of (32). They showed maximal stimulation of growth at concen- autocrine and paracrine growth factors. In normal breast lobules, trations of E 2 that in vivo would span the range seen in pre- ER+ cells do not divide but signal to adjacent ER- ones to do menopausal women (10 -1~ to 10 -9 M). Basal cell growth was so (28). Early in the malignant process, it appears that ER+ seen at low E 2 concentrations (10- ~ M), and inhibition of cells acquire the ability to divide, and growth factors that puta- growth was seen at high concentrations, analogous to high-dose tively act by a paracrine mechanism in the normal breast may estrogen treatment in patients (10 -5 to 10 -6 M; Fig. 4). Using act by autocrine (and paracrine) mechanisms in malignant tu- MCF-7 cells, Masamura et al. (33) showed that the E 2 dose- mors (29). This change in tumor cells also appears to allow them response curve could be shifted to the left if the cells were to adapt to the prevailing estrogen concentrations, whereas there grown in serum-free medium as devoid as possible of any E 2. is probable tight regulation of responsiveness in the normal The MCF-7 cells initially failed to grow when estrogen was breast. Adaptation to the prevailing estrogen concentrations is withdrawn, but after a few weeks, they returned to the growth seen when ER+ tumors that have an intact receptor grow in the rate of wild-type cells. When the E 2 dose-response curve was breast and then are detected clinically. At low postmenopausal reassessed, it had shifted markedly to the left. Maximal growth estrogen concentrations (10-tl to 10-1o M), normal breast cells stimulation occurred at 10 -14 M E2, whereas concentrations of do not proliferate, whereas tumors proliferate in response to E e that would be regarded as physiological in vivo (10 -1~ M) even such low concentrations. Altering the serum estrogen con- were growth inhibitory. These elegant experiments show the centration downward by the AIs (or upward by high-dose es- enormous range of E 2 concentrations under which human re- trogens) initially causes inhibition of growth. There is strong ceptor-positive cells are able to proliferate (10 -14 to 10 -9 M). evidence that tumors can then adapt to the new estrogen con- Given that in vivo tumors can adapt after an initial inhibition of centration. For example, a response may occur after ovarian growth by proliferating in the presence of high-dose estrogens, ablation: when the tumor regrows, a further response may be it is likely that the E 2 concentrations in which tumors can grow obtained by lowering the E 2 concentration [E2] further with an either in vitro or in vivo range from 10 -14 as shown by AI. When there is a response to high-dose estrogens, a further Masamura et al. (33) to about 10 -7 to 10 -6 M, which is response may be obtained on progression by simply stopping estimated to be the level of estrogen attained during high-dose treatment (30). Such WRs suggest that the tumor gradually treatment (Fig. 5). adapts to high-dose estrogen and then becomes stimulated by an Reddel and Sutherland (32) also demonstrated a dose- initially growth-suppressive estrogen concentration (31). response curve for tamoxifen in T47D cells (Fig. 4). This was Changes in dose-response curves for E 2 can be generated very similar to the E 2 dose-response curve, with stimulation of

New B {A C AI Old HRT-post E2 AI premenopausal deprived\ Post TE2 .9

L_w

H " L I H I 1 I I I 10 -14 10 -9 10 -6 10-15 10-14 10-11 10-10 10-9 10-8 10-7 10-6 10-s [estrogen] Concentration of estradiol Fig. 5 Summary dose-response curves for E2 with MCF-7 cells in vitro Arrows indicate [change] during endocrine therapy and potentially in patients. A, wild-type MCF-7 cells with maximal Fig. 6 Range of concentrations that human mammary tumor cells can proliferation at physiological estrogen concentrations. B, curve for es- proliferate in response to E 2 deprived data. Small changes from the trogen-deprived MCF-7 cells as described in Ref. 33. The arrow points postmenopausal concentrations (3 • 10 -71 M) induced by AIs can cause to a concentration that was inhibitory to B cells but is stimulatory for A responses. On the right are the putative concentrations of "estrogens" cells. C, probable dose-response curve when there is high-dose estrogen- seen during high-dose therapy. Tamoxifen at this concentration can also induced proliferation of tumors in patients. Stimulation at this concen- stimulate growth. tration is surmised from reports of WRs to high-dose estrogens.

growth at low concentrations (10 -1~ to 10 -9 M) and inhibition estrogen) on two occasions and to the left (two AIs) on two at 10 -6 to 10 -5 M, suggesting that under the condition of occasions. Unusually, it remains sensitive to all these changes. culture, tamoxifen behaves like an estrogen. Low-dose stimula- Usually tumors are either resistant de novo (this probability can tion of growth in vivo by tamoxifen may account for the tumor be assessed by looking at the response rates to preoperative flare phenomenon (34). WRs can be demonstrated when, after tamoxifen; Ref. 37) or acquire resistance during adjuvant ther- an initial response to tamoxifen, the drug is stopped at tumor apy or therapy for advanced disease. For example, approxi- progression, and thus it appears that tumors are capable of mately 40% of tumors are resistant at relapse; of those that adapting to tamoxifen as well as E 2 (31). Tamoxifen stimulation respond, 60% will be resistant to a second endocrine therapy. of MCF-7 cell growth can also be demonstrated when these cells Thus, as we continually see in the clinic, there is an inexorable are grown in nude mice. After an initial period of growth trend toward resistance even in initially responsive tumors. inhibition, tumor growth is stimulated by tamoxifen and can be Treating patients with endocrine therapy continuously, as is our reversed by the pure antiestrogen ICI 182,780 (35, 36). custom, is likely to be the most rapid way to induce such The range of concentrations of estrogen under which tu- resistance. mors can proliferate is illustrated in Fig. 6. Endocrine treatments With the new series of endocrine therapies that we now (e.g., ovarian ablation and aromatase inhibition) shift the con- have, we are in a position to investigate ways to minimize the centration of estrogen down, resulting in responses in sensitive trend toward resistance by using the agents we have creatively tumors. Changes in estrogen dose-response curves (for this and to answer three important questions: (a) can we increase the purpose, we assume tamoxifen is an estrogen) might change response rate at relapse; (b) can we increase the duration of during treatment of a tumor to the left and to the right (Fig. 5). response; and (c) can we prevent relapse by using better ap- Initially, the tumor grows in response to postmenopausal serum proaches to adjuvant therapy? estrogen concentrations, which in the United Kingdom are a geometric mean of about 3 X 10-~1 M. The tumor is excised Can We Increase the Response Rate in surgically and shown to be ER+, and the putative micrometas- Advanced Disease? tases are treated with tamoxifen (say, 10 -6 M). After 5 years Tamoxifen has been the first-line treatment for advanced with no relapse, tamoxifen treatment is stopped, but at, say, 8 disease for many years, giving clinical benefit in approximately years, there is a relapse in bone. These metastases will be 50% of patients with ER+ tumors. Recent randomized trials in growing in response to the postmenopausal E 2 concentration of which potent AIs were compared with tamoxifen show that the about 3 • 10-11 M. The patient is then treated with a potent AI, response rate may be increased a little using either anastrozole, which reduces E 2 concentration further to 1 x 10-]J M. There letrozole, or exemestane first line. The results of a trial of ICI is a response, but after 18 months, tumor progression occurs at 182,780 versus tamoxifen will soon be available, and it is hoped this concentration of E 2, and hence the E2 concentration is that the pure antiestrogen will also give higher response rates. It changed to 10 .7 to 10 .6 M with high-dose estrogens. After a is not known why tamoxifen is less effective, but it is possible further response, the patient is treated either by withdrawal of that some tumors respond to tamoxifen as a growth agonist de treatment or with a non-cross-resistant AI and obtains another novo as first treatment for advanced breast cancer. We and response. Thus, it is likely that this tumor has had its dose- others have reported that there is a small group of tumors that do response curve shifted to the right (tamoxifen and high-dose not respond to first-line tamoxifen treatment but respond to

second-line endocrine therapy, indicating that tamoxifen does A ER+ve X months not produce responses in all potentially responsive tumors. De relapse E2 SERM nil novo agonism seems a reasonable explanation for this phenom- [E2] enon, and the higher response rate to other agents may be At relapse because they are not tumor agonists (AIs and ICI 182,780). '[E2]' Given the endocrine therapies available and the ones in development (GW5683, SR16234, and ZK191703), it is unlikely that we can increase the first-line response rate further. In the 40% AI LHRH agonist nil L of tumors that are resistant to therapy, proliferation may be C driven by growth factors that act by inducing phosphorylation of LHRH a~lonist ER. The addition of inhibitors of these pathways, e.g., EGF tyrosine kinase inhibitors or HER-2 receptor antibodies, may r-'--Alll E221E23 allow endocrine agents to become active, an approach that AI2 / [Ez] ,1. [Ez] 1" E21 I warrants additional studies, which are in fact ongoing. Alterna- tively, synthesis of ER may have been repressed by gene meth- ylation because of the time the original measurement of ER was Fig. 7 Potential ways to prevent resistance. A, assume that [E2] is the made on the primary tumor. Treatment with demethylating serum E2 concentration at relapse in a patient with an ER- tumor. agents may be effective in reversing endocrine insensitivity. Standard treatment is to lower [E2], which, if prolonged, leads to resistance. Resistance may be circumvented if treatment is changed to raise [E2] by stopping treatment with estrogen or a SERM; X may be 3-6months. B, instead of maximal reduction of [E2], use sequential AIs Can We Prolong Response Duration in of increasing potency. C, instead of initial use of high-dose estrogens, Advanced Disease? gradually increase the dose over time. Even if tumors respond, the median duration of response to first-line endocrine therapy is almost always less than 2 years. A few patients may benefit from multiple responses, but these appear to show a detrimental effect (39). Fig. 6 shows that the women must endure the stress of repeated tumor progression and worry whether a further response is attainable. We would relatively small falls in serum E 2 associated with ovarian abla- wish not only to prolong responses but also to eliminate the tion or AI treatment result in responses. Additive estrogen is progression/response cycle currently seen. This is a difficult usually given at doses that are likely to be near or equivalent to the 10 -6 M concentration of tamoxifen. But there are a whole problem because we do not have a clear idea of the cellular range of intermediate concentrations from the premenopausal mechanisms involved, but if this cycle is due to shifts in the maximum of 10 -9 to 10 -6 or 10 -7 M, which could be explored estrogen dose-response curve, it is possible that administering as therapy in alternating or dose-escalating approaches as de- endocrine therapy continuously may act to induce endocrine scribed above. resistance. It may be the fastest way to shift the dose-response curve of the tumor to adapt to the new concentration of hormo- Clinical trials of these approaches will not be easy to nal agent. Also, treating until resistance appears may allow mount, not only because of potential patient and investigator resistance, but also because drug companies who finance many about half of tumors to change to complete resistance to endocrine therapy. A reasonable working hypothesis is that resist- of our large randomized trials are unlikely to be interested. Trials of sequential therapy of SERMs and AIs have been ance may be delayed and duration of response may be prolonged by changing treatment before the tumor adapts to the prevailing performed for many years. We know that ICI 182,780 will be effective after tamoxifen failure (15, 16) and that an AI with a concentration of estrogen or, in the case of tamoxifen, antiestrogen. different mechanism of action or greater potency in lowering Several strategies could be tested in clinical trials in pa- [E2] will be effective when used sequentially. Changing treat- tients with ER+ tumors at first relapse. Treatments that lowered ment before progression does not, therefore, seem an enormous or increased effective estrogen levels could be alternated, say, at step to take. However, the duration of each part of intermittent 3-month intervals. Alternatively, with the range of available therapy is an open question. Tumor markers may not be of much use because when they begin to rise it is likely that the tumor has AIs, estrogen concentrations could be lowered in a stepwise fashion or, with estrogen, increased in a stepwise fashion se- already adapted to the prevailing E 2 concentration. However, quentially (Fig. 7). Although we treat patients with large doses they may help with modeling the optimal time to use each of estrogen (DES, 5 mg three times per day in our study), lower treatment. Phase III trials comparing standard sequential (i.e., treatment at progression) with shorter-period sequential therapy doses have not been systematically studied. Many years ago, Stoll (38) reported responses to low-dose components of the oral will be needed to evaluate this new approach. contraceptive pill (lynestrol), suggesting that a small increase in estrogen concentration might be sufficient to obtain a first Prevention of Relapse by Better Use of Adjuvant response. A report of WRs in four patients who relapsed on Endocrine Therapy HRT after surgery for breast cancer suggests that in postmeno- As illustrated in Fig. 3, adjuvant endocrine therapy con- pausal women, the small increase in E 2 produced by HRT may sisting of 5 years of tamoxifen in patients with ER+ tumors be adequate adjuvant therapy and may be the reason why gives only modest results. In the 15-year data from the overview case-control studies of the use of HRT after surgery do not (25), 67% of patients in the no-treatment control arm did not

Table 4 Potential sequences of treatment for a postmenopausal or (3') ICI 182,780 is equivalent to anastrozole as second-line premenopausal patient depending on the stage of the disease that treatment for advanced disease. treatment w,as initiated (g) There appears to be little to choose between the new Prevention Neoadjuvant Adjuvant Adv 1" Adv2 AIs at present. Postmenopausal patients (h) Little cross-resistance between tamoxifen and ICI Ral/tam 182,780 was seen in two large trials. A/L Tam Exe 182 The clinical situation will perhaps be clarified when we Tam A/L 182 have the results of the ATAC trial. It is possible that anastrozole A/L 182 Premenopausal patients will be superior to tamoxifen or the combination of these agents Ral/tam as adjuvant therapy. If this is the case, an AI will become the Z + tam A/L 182 Exe treatment of choice as adjuvant therapy. Soon we will have the Tam A/L 182 results of a randomized trial of tamoxifen versus ICI 182,780 as A/L 182 first-line treatment for advanced disease. With an AI as optimal a Adv 1, first line; Adv 2, second line; A, Arimidex; L, Letrozole; treatment for adjuvant disease and possibly ICI 182,780 as Z, Zoladex; 182, ICI 182780 (Fulvestrant). optimal treatment for first-line advanced disease, tamoxifen and other AIs may be relegated to second- and third-line therapies for advanced breast cancer together with estrogens.

relapse and thus would not have benefited from adjuvant therapy. Of the 33% of patients who relapsed, only just over Conclusions one-third of these relapses would be preventable with tamox- The number of new SERMs and AIs we have available ifen, leaving two-thirds that would not be prevented by treat- now is exciting, especially because we have data that indicate a ment. AIs and ICI 182,780 improve a little compared with degree of non-cross-resistance between classes of agents within tamoxifen because they lack agonist activity. However, it may the SERM and AI groups. However, although we can produce be more appropriate to test sequential approaches. These are multiple remissions in a minority of patients with ER+ ad- being tested by several groups in adjuvant studies in which vanced breast cancer, the great challenge is to prevent relapse by tamoxifen is changed to an AI after 2-3 years of the 5-year improving endocrine measures in the first instance and to in- period of adjuvant therapy. The reverse sequence is also being crease the numbers of patients who benefit from endocrine tested. For the reasons outlined above, it is likely that sequential therapy when they have had the misfortune to relapse. Conven- approaches will be superior to the continuous use of a SERM or tional sequential approaches with new SERMs and AIs will an AI. A major question is whether shortening the interval undoubtedly improve outcomes. However, the hypothesis that between changes of adjuvant therapy to 3-6 months will be changing treatment before overt progression may markedly im- superior to our standard approaches. prove endocrine therapy needs to be tested.

Conventional Sequential Therapy: Which Is the Open Discussion Best Sequence? Dr. Steven Come: I wonder what patients would feel like The use of estrogens and WRs aside, what might be the if they were treated with pharmacological doses of estrogens. optimal sequence for the treatments that are now commonly Dr. Howell: Well, they should feel great because you're used or are in late clinical trials? The sequence is different for not going to give huge doses. We need to find out what happens premenopausal and postmenopausal patients because of the between 10 -1~ and 10 -7 M. It may well be that you could just added possibility of ovarian ablation for the former group. Also, give HRT. the sequence may be different according to the point in the Dr. Per Lonning: I can add some comments about the course of breast cancer at which therapy is initiated (e.g., pre- high-dose estrogens, because I treated many of these patients vention, neoadjuvant, adjuvant, or advanced disease). Potential myself. There were some striking phenomena. One was that sequences are shown in Table 4. These take into account data they very often responded very quickly. I still have some pa- from current trials and our knowledge of cross-resistance be- tients who are on high-dose estrogens more than 2 years after tween and within SERMs and AIs. Clearly the sequences are they got a complete remission. tentative in the light of the (surprising) paucity of data available. Dr. Kent Osborne: In my minimal experience with it, These data may be summarized as follows: patients on high-dose DES, 15 rag/day, feel the best of any (a) Tamoxifen and raloxifene are potentially useful preven- endocrine therapy. Is that your experience? tive agents, particularly in high-risk younger women. Dr. James Ingle: Initially. About half will retain fluid, and (b) AIs appear to be superior to tamoxifen in downstaging then you get incontinence in about 40% on long-term high dose. tumors preoperatively. But I think you're right. If you go up on the dose over about a (c) Five years of tamoxifen still remains the treatment of week, you actually can get around some of the nausea. choice for adjuvant therapy. Dr. Osborne: I think it would be kind of a bumpy ride (d) AIs are superior to tamoxifen for first-line treatment for going from high-dose estrogen down to an AI, and you have to advanced disease. alternate frequently enough to avoid resistance to one pattern or (e) AIs are superior to megestrol acetate for second-line the other. therapy for advanced disease. Dr. Howell: Well, that's right. The question is how much

you have to give. Going from moderate-dose estrogen down to postmenopausal patients with metastatic breast cancer. J. Clin. Oncol., an AI may well be tolerable. It's a matter of doing the clinical 13: 2556-2566, 1995. experiments if you feel that is an approach to take. 10. Connor, C. E., Norris, J. D., Broadwater, G., et al. Circumventing Dr. Lonning: When you say that if anastrozole is superior tamoxifen resistance in breast cancers using antiestrogens that induce conformational changes in the estrogen receptor. Cancer Res., 61: in the ATAC results, it could kill the sequential trial with 2917-2922, 2001. exemestane, you could say the other way around. If the sequen- 11. Bentrem, D., Dardes, R., Liu, H., et al. Molecular mechanism of tial therapy turns out to be better than tamoxifen, that kills the action at oestrogen receptor a of a new clinically relevant antiestrogen control arm in the ATAC trial and you have to reject the whole (GW7604) related to tamoxifen. Endocrinology, 142: 838-846, 2001. trial. 12. Buzdar, A. U., O'Shaughnessy, A., Hudis, C., et al. Preliminary results of a randomised double-blind Phase II study of the selective Dr. Angela Brodie: We have models of these things. oestrogen receptor modulator (SERM) arzoxifene (AZ) in patients with These agents all work quite well, actually. If you alternate them locally advanced or metastatic breast cancer. Proc. Am. Soc. Clin. back and forth they're about equivalent. We've also tried the Oncol., 20: 45a, 2001. on-and-off scheme. However, continuous letrozole treatment 13. Wakeling, A. E., and Bowler, J. ICI 182780, a new antioestrogen was the best and of longest duration in our animals. Once we with clinical potential. J. Steroid Biochem. Mol. Biol., 43: 173-177, 1992. withdraw letrozole, estradiol is produced again. We were quite 14. Howell, A., DeFriend, D., Robertson, J., et al. Response to a surprised to find that giving letrozole a second time actually specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer. caused responses. These tumors were also very responsive to Lancet, 345: 29-30, 1995. fulvestrant, actually even more than to letrozole in this setting. 15. Howell, A., Robertson, J. F. R., Quaresma, A. J., et al. Comparison Dr. Come: How much confidence do we have in these of efficacy and tolerability of fulvestrant (Faslodex) with anastrozole models in terms of predicting? (Arimidex) in post-menopausal (PM) women with advanced breast cancer (ABC): preliminary results. Breast Cancer Res. Treat., 64: 27, Dr. Brodie: Well, most of the earlier studies we've done 2000. have turned out to be predictive in the clinic. The first-line 16. Osborne, C. K. A double-blind randomised trial comparing the treatment with letrozole, for example, was better than tamox- efficacy and tolerability of Faslodex (fulvestrant) with Arimidex (anas- ifen. trozole) in post-menopausal (PM) women with advanced breast cancer Dr. Come: Since we can't do an infinite number of trials, (ABC). Breast Cancer Res. Treat., 64: 27, 2000. do we have some really good models that are predictive that will 17. Griffiths, C. T., Hall, T. C., Saba, Z., et al. Preliminary trial of aminoglutethimide in breast cancer. Cancer (Phila.), 32: 31-37, 1973. allow us to narrow the questions a great deal and then do a small number of big, meaningful trials with blocks? 18. Buzdar, A. U., Jonat, W., Howell, A., et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with Dr. Brodie: We'll have to do the trials, of course, but these advanced breast carcinoma: results of a survival update based on a could be focused on predictions from the model. combined analysis of data from two mature Phase III trials. Arimidex Dr. Howell: We can't do every trial. Study Group. Cancer (Phila.), 83:1142-1152, 1998. Dr. Kathleen Pritchard" We want to do the right trials. 19. Dombernowsky, P., Smith, I., Falkson, G., et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double blind randomized trial showing a dose effect and tolerability compared with References megestrol acetate. J. Clin. Oncol., 16: 453, 1998. 20. Kaufmann, M., Bajetta, E., Dirix, L. Y., et al. Exemestane is 1. Haddow, A., Watkinson, J., Patterson, E., et al. Influence of synthetic superior to megestrol acetate after tamoxifen failure in postmenopausal oestrogens upon advanced malignant disease. Br. Med. J., 2: 393-398, women with advanced breast cancer: results of a Phase III randomized 1944. double-blind trial. The Exemestane Study Group. J. Clin. Oncol., 18: 2. Walpole, A. L., and Patterson, E. Synthetic oestrogens in mammary 1399, 2000. cancer. Lancet, 2: 783-786, 1949. 21. Nabholtz, J. M., Bonneterre, J., Buzdar, A., et al. Preliminary 3. Matelski, H., Greene, R., Huberman, M., et al. Randomized trial of results of two multicentre trials comparing the efficacy and tolerability estrogen versus tamoxifen therapy for advanced breast cancer. Am. J. of Arimidex (anastrozole) and tamoxifen (TAM) in post-menopausal Clin. Oncol., 8: 128-133, 1985. women with advanced breast cancer (ABC). Breast Cancer Res. Treat., 4. Peethambaram, P. P., Ingle, J. N., Suman, V. J., et al. Randomised 57: 31, 1999. trial of diethylstilboestrol versus tamoxifen in postmenopausal women 22. Milla-Santos, A., Milla, A., Rallo, L., et al. Anastrozole versus with metastatic breast cancer. An updated analysis. Breast Cancer Res. tamoxifen in hormonodependent advanced breast cancer. A Phase II Treat., 54: 117-122, 1999. randomised trial. 23 ra San Antonio Breast Cancer Symposium. Breast 5. Lonning, P. E., Anker, P., Taylor, P. D., et al. High-dose estrogen Cancer Res. Treat., 64: A173, 2000. treatment in postmenopausal breast cancer patients heavily exposed to 23. Mouridsen, H., Gershanovich, M., Sun, Y., et al. Superior efficacy endocrine treatment for advanced breast cancer. Breast Cancer Res. of letrozole versus tamoxifen as first-line therapy for postmenopausal Treat., 67:111-116, 2001. women with advanced breast cancer: results of a Phase III study of the 6. Cole, M. P., Jones, C. T., and Todd, I. D. A new anti-oestrogenic Intemational Letrozole Breast Cancer Group. J. Clin. Oncol., 19: 2596- agent in late breast cancer. An early clinical appraisal of ICI 46474. 2606, 2001. Br. J. Cancer, 25: 270-275, 1971. 24. Paridaens, R., Dirix, L. Y., Lohrisch, C., et aI. Promising activity 7. Howell, A., Downey, S., and Anderson, E. New endocrine therapies and safety of exemestane (E) as first line hormonal therapy (HT) in for breast cancer. Eur. J. Cancer, 32A: 576-588, 1996. metastatic breast cancer (MBC) patients: final results of an EORTC 8. Holli, K., Valavara, R., Blanco, G., et al. Safety and efficacy results randomised Phase II trial. Breast Cancer Res. Treat., 64: 52, 2000. of a randomised trial comparing adjuvant toremifene and tamoxifen in 25. Tamoxifen for early breast cancer: overview of the randomised postmenopausal patients with node positive breast cancer. Finnish trials. Early Breast Cancer Trialists' Collaborative Group (EBTCG). Breast Cancer Group. J. Clin. Oncol., 18: 3487-3494, 2000. Lancet, 351: 1451-1467, 1998. 9. Hayes, D. F., Van Zyl, J. A., Hacking, A., et al. Randomized 26. Howell, A., Mackintosh, J., Jones, M., et al. The definition of the comparison of tamoxifen and two separate doses of toremifene in "no change" category in patients treated with endocrine therapy and

chemotherapy for advanced carcinoma of the breast. Eur. J. Cancer Clin. 37. Howell, A., Anderson, E., Blamey, R., et al. The primary use of Oncol., 24: 1567-1572, 1988. endocrine therapies. In: H-J. Senn, R. Gelber, A. Goldhirsch, and 27. Robertson, J. F. R., Howell, A., Buzdar, A., et al. Static disease on B. Thtirlimann (eds.), Recent Results in Cancer Research 152: Adjuvant anastrozole provides similar benefit as objective response in patients Therapy in Breast Cancer VI, pp. 227-244. Heidelberg: Springer-Ver- with advanced breast cancer. Breast Cancer Res. Treat., 58: 157-162, lag, 1998. 1999. 38. Stoll, B. A. Effect of Lyndiol, an oral contraceptive, on breast 28. Clarke, R. B., Howell, A., Potten, C. S., et al. Dissociation between cancer. Br. Med. J., 1: 150-153, 1967. steroid receptor expression and cell proliferation in the human breast. 39. Dhodapkar, M. V., Ingle, J. N., and Ahmann, D. L. Estrogen Cancer Res., 57." 4987-4991, 1997. replacement therapy withdrawal and regression of metastatic breast 29. Shoker, B. S., Jarvis, C., Clarke, R. B., et al. Abnormal regulation cancer. Cancer (Phila.), 75: 43-46, 1995. of the oestrogen receptor in benign breast lesions. J. Clin. Pathol., 53: 40. Labile, F., Labile, C., Belanger, A., et al. EM-652 (SCH 57068), a 778-783, 2000. third generation SERM acting as pure antiestrogen in the mammary 30. Huseby, R. A. Estrogen therapy in the management of advanced gland and endometilum. J. Steroid Biochem. Mol. Biol., 69: 51-84, breast carcinoma. Am. J. Surg., 20:1 t2, t954. 1999. 31. Howell, A., Dodwell, D., Anderson, H., and Redford, J. Response 41. Gradishar, W., Glusman, J., Lu, Y., et aL Effects of high dose after withdrawal of tamoxifen and progestogens in advanced breast cancer. Ann. Oncol., 3:611-617, 1992. raloxifene in selected patients with advanced breast carcinoma. Cancer (Phila.), 88: 2047-2053, 2000. 32. Reddel, R. R., and Sutherland, R. L. Effects of pharmacological concentrations of estrogens on proliferation and cell cycle kinetics of human 42. Baselga, J., Llombart-Cussac, A., Bellet, M., et al. Randomised breast cancer cell lines in vitro. Cancer Res., 47: 5323-5329, 1987. double blind Phase 2 study of a selective estrogen receptor modulator 33. Masamura, S., Santner, S. J., Heitjan, D. F., et al. Estrogen depri- (SERM) in patients with locally advanced or metastatic breast cancer vation causes estradiol hypersensitivity in human breast cancer cells. (LAMBC). Breast Cancer Res. Treat., 57: A25, 1999. J. Clin. Endocrinol. Metab., 80: 2918-2925, 1995. 43. Munster, P. N., Buzdar, A., Dhugra, K., et al. Phase I study of a 34. Clarysse, A. Hormone-induced tumor flare. Eur. J. Cancer Clin. third generation SERM LY353381.HCL in metastatic breast cancer. Oncol., 21: 545-547, 1985. J. Clin. Oncol., 19: 2002-2009, 2001. 35. Gottardis, M. M., Jiang, S. Y., Jeng, M. H., and Jordan, V. C. 44. Lonning, P. E., Bajetta, E., Murray, R., et al. Activity of exemestane Inhibition of tamoxifen stimulated growth of an MCF-7 tumor variant in in metastatic breast cancer after failure of nonsteroidal aromatase inhib- athymic mice by novel steroidal antiestrogens. Cancer Res., 49: 4090- itors: a Phase II trial. J. Clin. Oncol., 18: 2234-2244, 2000. 4093, 1989. 45. Carlini, P., Frassoldati, A., Casali, A., et al. Formestane (FOR) a 36. Osborne, C. K., Jarman, M., McCague, R., et al. The importance of steroidal aromatase inhibitor (SAI) after failure of nonsteroidal aro- tamoxifen metabolism in tamoxifen-stimulated breast tumor growth. matase inhibitors (NSAI) (anastrozole: ANZ and letrozole:LTZ): is a Cancer Chemother. Pharmacol., 34: 89-95, 1994. clinical benefit still possible? Ann. Oncol., 11 (Suppl. 4): 35, 2000.

Anthony Howell

Clin Cancer Res 2001;7:4402s-4410s.

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